SUMMARY OF WORK The expression of the gene coding for the contractile protein a-myosin heavy chain declines markedly with advancing aging, as does the expression of a number of other cardiac-specific genes that are significantly upregulated in the hyperthyroid animal. In contrast, the contractile protein b-myosin heavy chain increases markedly with age. We have discovered that components of the heterodimeric nuclear transcription factors that regulate these genes, i.e., two thyroid hormone receptor isoforms and one retinoid X receptor isoform, decline with age suggesting that changes in thyroid hormone nuclear factors might play a role in their regulation. We have recently examined the ability of these nuclear factors to bind to those areas of the DNA known to be regulated by them. What we have found is that there is no real change in the relative capacity to bind to these sequences with aging, at least in vitro. Alternatively, we have found one DNA binding domain in the gene encoding b-myosin heavy chain that has a marked increase in binding in the aged myocardium. Binding to this site in in vitro models of cardiac hypertrophy has been shown to increase this gene's transcriptional activity. We are now examining the possibility that this site may be important in the aging process of the myocardium.